Yue L, Feng J, Gaspo R, Li G R, Wang Z, Nattel S
Department of Medicine, Montreal Heart Institute, Quebec, Canada.
Circ Res. 1997 Oct;81(4):512-25. doi: 10.1161/01.res.81.4.512.
Rapid electrical activation, as occurs during atrial fibrillation (AF), is known to cause reductions in atrial refractoriness and in adaptation to heart rate of the atrial refractory period, which promote the maintenance of AF, but the underlying ionic mechanisms are unknown. In order to determine the cellular and ionic changes caused by chronic atrial tachycardia, we studied right atrial myocytes from dogs subjected to 1, 7, or 42 days of atrial pacing at 400/min and compared them with myocytes from sham-operated dogs (pacemaker inserted but not activated). Rapid pacing led to progressive increases in the duration of AF induced by bursts of 10-Hz stimuli (from 3 +/- 2 seconds in sham-operated dogs to 3060 +/- 707 seconds in dogs after 42 days of pacing, P < .001) and reduced atrial refractoriness and adaptation to rate of the atrial refractory period. Voltage-clamp studies showed that chronic rapid pacing did not alter inward rectifier K+ current, rapid or slow components of the delayed rectifier current, the ultrarapid delayed rectifier current, T-type Ca2+ current, or Ca(2+)-dependent Cl- current. In contrast, the densities of transient outward current (Ito) and L-type Ca2+ current (ICa) were progressively reduced as the duration of rapid pacing increased, without concomitant changes in kinetics or voltage dependence. In keeping with in vivo changes in refractoriness, action potential duration (APD) and APD adaptation to rate were decreased by rapid pacing. The response of the action potential and ionic currents flowing during the action potential (as exposed by action-potential voltage clamp) to nifedipine in normal canine cells and in cells from rapidly paced dogs suggested that the APD changes in paced dogs were largely due to reductions in ICa. We conclude that sustained atrial tachycardia reduces Ito and ICa, that the reduced ICa decreases APD and APD adaptation to rate, and that these cellular changes likely account for the alterations in atrial refractoriness associated with enhanced ability to maintain AF in the model.
快速电激活，如在心房颤动（AF）期间发生的那样，已知会导致心房不应期缩短以及心房不应期对心率的适应性降低，这会促进房颤的维持，但其潜在的离子机制尚不清楚。为了确定慢性心房心动过速引起的细胞和离子变化，我们研究了以400次/分钟的频率进行1、7或42天心房起搏的犬的右心房肌细胞，并将它们与假手术犬（植入起搏器但未激活）的肌细胞进行比较。快速起搏导致由10Hz刺激脉冲诱发的房颤持续时间逐渐增加（从假手术犬的3±2秒增加到起搏42天后犬的3060±707秒，P<.001），并降低了心房不应期以及心房不应期对心率的适应性。电压钳研究表明，慢性快速起搏不会改变内向整流钾电流、延迟整流电流的快速或慢速成分、超快速延迟整流电流、T型钙电流或钙依赖性氯电流。相反，随着快速起搏持续时间的增加，瞬时外向电流（Ito）和L型钙电流（ICa）的密度逐渐降低，而动力学或电压依赖性没有相应变化。与体内不应期的变化一致，快速起搏降低了动作电位持续时间（APD）和APD对心率的适应性。正常犬细胞和快速起搏犬细胞动作电位及动作电位期间流动的离子电流（通过动作电位电压钳显示）对硝苯地平的反应表明，起搏犬的APD变化主要是由于ICa的降低。我们得出结论，持续性心房心动过速会降低Ito和ICa，降低的ICa会减少APD和APD对心率的适应性，并且这些细胞变化可能解释了与该模型中房颤维持能力增强相关的心房不应期改变。
